Granules, tablets and granulation

ABSTRACT

The invention provides, inter alia, a method for producing granules from a powder, characterized in that a low compaction force is applied to the powder to produce a compacted mass comprising a mixture of fine particles and granules and separating fine particles from the granules by entraining the fine particles in a gas stream. Also provided are apparatus for use in the process and tablets formed by compression of the resultant granules.

This application is a divisional of application Ser. No. 11/979,530filed on Nov. 5, 2007 now U.S. Pat. No. 8,052,999, and for whichpriority is claimed under 35 U.S.C. §120. This application also claimspriority under 35 U.S.C. §119 on Finnish Application No. 20060990, filedNov. 10, 2006; Finnish Application No. 20061146, filed Dec. 21, 2006;and Finnish Application No. 20070521, filed Jul. 2, 2007; the entirecontents of all of which are hereby incorporated by reference in theirentirety.

TECHNICAL FIELD OF INVENTION

The invention relates to granules and tablets and method and apparatusfor their production.

BACKGROUND OF THE INVENTION

Tablets are one of the most frequently employed delivery forms for mostmedicinal preparations. This situation can be explained by the fact thatthis dosage form allows for accurate dosage of the active component ofthe medicinal formulation. Furthermore, handling and packaging areeasier and shelf life and stability of these preparations are generallybetter than those of other formulations.

These same arguments also explain the reason why tablets are often usedas media for other applications such as food, including confectioneryproducts, aromas or sweeteners, detergents, dyes or phytosanitaryproducts.

A solid bulk of granulate mass, which is necessary for manufacturingtablets, can be manufactured using two main processes, wet granulationor dry granulation. Tablets may also be manufactured using directcompression. Direct compression relates to the tableting process itselfrather than preparation of the starting material.

In wet granulation, components are typically mixed and granulated usinga wet binder. The wet granulates are then sieved, dried and optionallyground prior to compressing into tablets. Wet granulation is usedextensively in the pharmaceutical industry although it has proven to bea difficult method, mainly because the liquids needed in the granule andtablet manufacturing process often have an adverse effect on thecharacteristics of the active pharmaceutical ingredients (APIs) and/oron the end product such as a tablet.

Dry granulation is usually described as a method of controlled crushingof precompacted powders densified by either slugging or passing thematerial between two counter-rotating rolls. More specifically, powderedcomponents that may contain very fine particles are typically mixedprior to being compacted to yield hard slugs which are then ground andsieved before the addition of other ingredients and final compression toform tablets. Because substantially no liquids are used in the drygranulation process, the issues related to wet granulation are avoided.Although dry granulation would in many cases appear to be the best wayto produce products such as tablets containing APIs, it has beenrelatively little used because of the challenges in producing thedesired kind of granules as well as managing the granulated material inthe manufacturing process. Known dry granulation methods, as well as theknown issues related to them are well described in scientific articles,such as the review article “Roll compaction/dry granulation:pharmaceutical applications” written by Peter Kleinebudde and publishedin European Journal of Pharmaceutics and Biopharmaceutics 58 (2004) atpages 317-326.

Direct compression is generally considered to be the simplest and themost economical process for producing tablets. However, it may only beapplied to materials that don't need to be granulated before tableting.Direct compression requires only two principal steps; i.e., the mixingof all the ingredients and the compression of this mixture. However,direct compression is applicable to only a relatively small number ofsubstances as the ingredients of the tablets often need to be processedby some granulation technique to make them compressible and/or forimproving their homogeneity and flow-ability.

A component of a tablet is usually described as being either anexcipient or an active ingredient. Active ingredients are normally thosethat trigger a pharmaceutical, chemical or nutritive effect and they arepresent in the tablet only in the amount necessary to provide thedesired effect. Excipients are inert ingredients that are included tofacilitate the preparation of the dosage forms or to adapt the releasecharacteristics of the active ingredients, or for other purposesancillary to those of the active ingredients.

Excipients can be characterized according to their function in theformulation as, for instance, lubricants, glidants, fillers (ordiluents), disintegrants, binders, flavors, sweeteners and dyes.

Lubricants are intended to improve the ejection of the compressed tabletfrom the die of the tablet-making equipment and to prevent sticking inthe punches.

Glidants are added to improve the powder flow. They are typically usedto help the component mixture to fill the die evenly and uniformly priorto compression.

Fillers are inert ingredients sometimes used as bulking agents in orderto decrease the concentration of the active ingredient in the finalformulation. Binders in many cases also function as fillers.

Disintegrants may be added to formulations in order to help the tabletsdisintegrate when they are placed in a liquid environment and so releasethe active ingredient. The disintegration properties usually are basedupon the ability of the disintegrant to swell in the presence of aliquid, such as water or gastric juice. This swelling disrupts thecontinuity of the tablet structure and thus allows the differentcomponents to enter into solution or into suspension

Binders are used to hold together the structure of the tablets. Theyhave the ability to bind together the other ingredients after sufficientcompression forces have been applied and they contribute to theintegrity of the tablets.

Finding the proper excipients for particular APIs and determining theproper manufacturing process for the combination of excipients and APIscan be a time-consuming job that may lengthen the design process of apharmaceutical product, such as a tablet significantly, even by years.

Both the dry and wet granulation methods of the prior art may producesolid bridges between particles within granules that may be undesirablefor example in that they lead to unsatisfactory subsequent tabletcharacteristics. The solid bridges may be caused by partial melting,hardening binders or crystallization of dissolved substances. Partialmelting may for example occur when high compaction force is used in drygranulation methods. When the pressure in the compaction process isreleased, crystallization of particles may take place and bind theparticles together. Introduction of hardening binders is common inpharmaceutical wet granulations when a binder is included in thegranulating solvent. The solvent forms liquid bridges, and the binderwill harden or crystallize on drying to form solid bridges between theparticles. Examples of binders which can function in this way arepolyvinylpyrrolidone, cellulose derivatives (e.g.carboxymethylcellulose) and pregelatinized starch. Substances, e.g.lactose, which can dissolve during a wet granulation process maysubsequently crystallize on drying acting as a hardening binder.

Electrostatic forces may also be important in causing powder cohesionand the initial formation of agglomerates, e.g. during mixing. Ingeneral they do not contribute significantly to the final strength ofthe granule. Van der Waals forces, however, may be about four orders ofmagnitude greater than electrostatic forces and can contributesignificantly to the strength of granules, e.g. those produced by drygranulation. The magnitude of these forces increases as the distancebetween particle surfaces decreases.

In addition to finding a practical manufacturing process for apharmaceutical product, validation of the manufacturing process isessential. Validation means that the process must be able to reliablyproduce a consistently acceptable and predictable outcome each time theprocess is used. Wet granulation methods are quite challenging to managein this respect. The wet granulation process is often quite vulnerableto small changes in manufacturing conditions. For example, variations inthe moisture content of starch in the manufacturing process after dryingmay produce a tablet that is too hygroscopic or which has a reducedshelf life. When a pharmaceutical product is being developed inlaboratory conditions, the conditions can be controlled relativelyeasily. However, the conditions available in mass productionenvironments are typically less accurately controllable thus makingvalidation of the manufacturing process a difficult and time consumingtask. The same can be said about direct compression methods where thequality of the final product depends on the physical properties of theAPI and excipients. A small change in such properties can result, forexample in segregation and flow-ability problems.

Because of the manufacturing and process validation issues related towet granulation and direct compression methods, it is desirable,particularly in the pharmaceutical industry, to use dry granulationtechniques whenever possible. However, the dry granulation methods knownin the prior art produce granules that are seldom usable in a tabletmanufacturing process. Conflicting process design parameters often leadto compromises where some qualities of the resulting granule product maybe good, but other desirable qualities are lacking or absent. Forexample, the flow characteristics of the granules may be insufficient,the non-homogeneity of the granules may cause segregation in themanufacturing process or capping in tablets, or some of the granules mayexhibit excessive hardness, all of which can make the tableting processvery difficult, slow and sometimes impossible. Furthermore, the bulkgranules may be difficult to compress into tablets. Alternatively oradditionally, the disintegration characteristics of the resultingtablets may be sub-optimal. Such problems commonly relate to thenon-homogeneity and granule structure of the granulate mass produced bythe compactor. For instance, the mass may have too high a percentage offine particles or some granules produced by the compactor may be toodense for effective tableting.

It is also well known in the art that in order to get uniform tabletsthe bulk to be tableted should be homogeneous and should have good flowcharacteristics.

In prior art dry granulation processes such as roll compaction, theresulting bulk is not generally homogeneously flowing, for examplebecause of the presence of relatively large (1-3 mm) and dense granulestogether with very small (e.g. 1-30 micrometers) particles. This cancause segregation as the large, typically dense and/or hard granules ofthe prior art flow in a different way to the fine particles when thegranulate mass is conveyed in the manufacturing process, e.g. duringtableting. Because of the segregation, it is often difficult to ensureproduction of acceptable tablets. For this reason, in the art there aresome known devices in which the small particles and sometimes also thebiggest particles are separated from the rest of the granules with thehelp of a fractionating device such as (a set of) vibrating screen(s).This process is generally complicated and noisy and the result is arelatively homogeneously flowing bulk where the granules are hard anddifficult to compress into tablets. Furthermore, the process ofseparating small particles from granules becomes very difficult if thematerial is sticky and the screen-size is not big enough. Generally inthis process the apertures of the screen must have a minimum dimensionof at least 500 μm.

Another problem which occurs in dry granulation methods of the prior artis the difficulty of preparing, in the development stage, a pilot bulkwhich is representative of the production bulk. Thus, the compactionforces and the other compaction parameters used at the laboratory scalecan be very different from those used at the production scale. As aresult the properties, e.g. flow-ability of the production bulk can bevery different from that which has been prepared in a pilot facility.One sieving method applicable in laboratory scale is air sieving. Oneconventional air sieve involves passing a powder through a mesh ofdefined size in order to exclude particles below the specified size (thedesired granules are retained above the mesh and the rejected particlespass below). Air is passed through the mesh to carry away the fineparticles. The problem with the air sieves of the prior art is thattheir capacity is not sufficient for industrial production of granulatemass. Furthermore, the air sieves that rely on mesh size in theseparation of rejected material often exclude desirable small granulesfrom the acceptable granulate mass when separating out the fineparticles from the mass.

Yet further, fragile granules may break in the sieving process whereundersize particles are sucked through the apertures of the sieve.

Patent application WO 99/11261 discloses dry-granulated granules thatmay comprise API only. In the method disclosed in the application, anair sieve known in the prior art is used for separating fine particles(particles and granules smaller than 150 or 125 micrometers) fromgranules comprising up to 100% of API. The sieving utilizes a sievewhose mesh size is about the maximum size of rejectable particles, e.g.150 micrometers. It seems that the granules of the disclosure have beencreated using relatively high compaction forces since the proportion offine particles (smaller than 125 micrometers) after compaction is atmost around 26 per cent (see table 1). The method results, followingsieving, in a flowing homogeneous granulate mass that would be expectedto comprise generally hard granules and that substantially is lackinggranules and particles smaller than 150 or 125 micrometers.

U.S. Pat. No. 4,161,516 teaches a composition for treating airwaydisease using soft tablets or granules for inhalation administration.The method of the patent is suitable for producing granules that aresoft enough to break apart in an airstream.

U.S. Pat. No. 6,752,939 teaches a method and an apparatus for predictingthe suitability of a substance for dry granulation by roller compactionusing small sample sizes.

U.K. Patent 1,558,153 discloses a method for producing organic dyematerial from finely divided particles by compressing said finelydivided particles to produce a coherent mass of material, comminutingsaid coherent mass of material, and recovering granular material in theparticle size range of 100-1000 microns from said comminuted material.The finest particles are removed by air flow.

We have now found an improved method of making granules and tablets. Themethod is applicable to a large variety of solid powder substances, e.g.APIs and excipients, as well as non-pharmaceutical products e.g. thoseused in the chemical and food industries.

BRIEF DESCRIPTION OF THE INVENTION

According to the invention, we provide a method for producing granulesfrom a powder, wherein a low compaction force is applied to the powderto produce a compacted mass comprising a mixture of fine particles andgranules and separating fine particles from the granules by entrainingthe fine particles in a gas stream.

The method will typically further comprise the step of collecting thegranules. As explained below, the method may typically be run as acontinuous process.

Suitably the process is carried out in the substantial absence ofliquid.

The powder, e.g. the APIs and/or excipients usable in pharmaceuticalindustry, to be used in the granulation process of the invention,generally comprises fine particles. Further, the powder may typicallyhave a mean particle size of less than 100, 50 or 20 micrometers. Thefine particles in the powder may typically have a minimum particle sizeof 2, 5 or 10 μm and maximum size of 150, 100 or 75 μm. The inventorsbelieve that the inventive ideas of the method disclosed herein may beapplicable to form granules also from powder whose minimum particle sizeis smaller than the typical minimum size mentioned above, e.g. 0.001,0.01 or 1 μm.

The mean particle size may be measured for example using a set ofsieves. In case of very fine powders, also microscopy may be used foranalyzing the particle sizes. The flowability of such powders isgenerally insufficient for e.g. tableting purposes. An exemplary methodfor determining sufficient flowability of a mass is disclosed in thedetailed description of FIG. 9.

Hence “fine particles” or “fines” are individual particles typicallyhaving a mean particle size of less than 100, 50 or 20 micrometers and amaximum size of 150, 100 or 75 μm.

When several fine particles (e.g. 3, 5, 10 or more) agglomerate to formgranules of maximum size of 150, 100 or 75 μm, they are referred to assmall granules. Granules larger than the maximum size are referred to as“acceptable granules”. Those granules that remain after fine particlesand/or small granules have been entrained by the gas stream, are called“accepted granules”.

The low compaction force may be provided for example using a rollercompactor. The roller compactor may be accompanied by an optional flakecrushing screen or other device, e.g. oscillating or rotating mill,suitable for producing granules from the compacted material. Theoptional step of employing a flake crushing screen or other device,will, if necessary, prepare the material for separation of fineparticles and/or small granules from other granules.

Thus typically the compaction force is applied to the powder by aprocess comprising use of a roller compactor to generate a ribbon ofcompacted powder which is broken up to produce granules e.g. by means ofa flake crusher. The flake crusher or similar device may permit theupper size of granules to be controlled e.g. by passing them through ascreen. The aperture size of the flake crushing screen may be e.g. 0.5mm, 1.0 mm or 1.2 mm.

The low compaction force may be adjusted to be at minimum such that atleast one, five, ten or fifteen percent of the powder substance becomesacceptable granules during compaction and/or fractionating steps, whilethe rest of the material remains fine particles and/or small granules.

If the compaction force used is too low, inventors have observed thatthe granules accepted by the process may be too fragile for e.g.tableting purposes. Such granules may also be too large, e.g. largerthan 3 mm. Fragile granules may not flow well enough or be strong enoughto be handled e.g. in a tableting process.

The maximum low compaction force may be adjusted so that 75 percent orless, 70 percent or less, 65 percent or less, 50 percent or less or 40percent or less, of the powder is compacted into acceptable granules andthe rest remains as fine particles and/or small granules. The maximumlow compaction force is typically up to 500%, 250% or 150% of a minimumlow compaction force.

For instance, the compaction force may be sufficiently low that 75% orless by weight of the powder is compacted into acceptable granuleshaving particle size larger than 150 μm (and/or a mean size of 100 μm orgreater) and the rest remains as fine particles and/or small granules.

The maximum and minimum low compaction forces will of course depend onthe particular compactor and powder used. Thus, for example the minimumlow compaction force may be adjusted so that it is the minimum possiblecompaction force, 15 kN, 20 kN or 30 kN in a Hosokawa™ (Osaka, Japan)Bepex Pharmapaktor L200/50P roller compactor. The maximum low compactionforce may also be adjusted so that it is 80 kN or less, 70 kN or less,60 kN or less or 45 kN or less in a Hosokawa™ Bepex PharmapaktorL200/50P roller compactor.

Typically a low compaction force is 60 kN or less e.g. 45 kN or less.Typically, a low compaction force is 16 kN or more.

The maximum low compaction force may also be adjusted so thatsubstantially no solid bridges are formed in the granules of theresulting mass e.g. due to heating of the mass. Some compactors known inthe art provide means for cooling the compacted material to alleviatethe heating issues introduced by use of high compaction forces. With themethod and system of the present invention, this precaution isunnecessary.

The compaction force may be adjusted using a method appropriate for thecompactor employed, for example by control of the rate of feed into thecompactor.

The gas stream may be provided by any suitable means, e.g. a suctionfan. The gas stream, e.g. air, may be directed through a fractionatingchamber. The gas stream separates at least some fine particles and/orsmall granules from the mass comprising acceptable granules, smallgranules and fine particles. The separated fine particles and/or smallgranules entrained in the gas stream may be transferred from thefractionating chamber to a separating device, e.g. a cyclone where thecarrier gas is separated from the fine particles and/or small granules.The fine particles and/or small granules may then be returned to thesystem for immediate re-processing (i.e. they are re-circulated forcompaction) or they may be placed into a container for laterre-processing.

Thus, conveniently, fine particles and/or small granules are separatedfrom the acceptable granules by means of an apparatus comprisingfractionating means. Desirably, the fractionating means comprises afractionating chamber.

As discussed in greater detail in the examples, the largest acceptablegranules exiting from the fractionating chamber are usually larger insize than the largest granules entering the fractionating chamber. Theinventors believe that a process whereby small granules and/or fineparticles agglomerate with larger granules takes place during theconveyance of the material through the fractionating chamber.

Suitably the direction of the flow of the gas stream has a componentwhich is contrary to that of the direction of flow of the compacted massin general and accepted granules especially. Typically the direction ofthe flow of the gas stream is substantially contrary to (e.g. around150-180° to), and preferably contrary to that of the direction of flowof the compacted mass.

The gas may, for example, be air (suitably dry air).

The fractionating means may comprise means to guide a gas stream intothe fractionating means, means to put the compacted mass into motion andmeans to guide removed fine particles and/or small granules entrained inthe gas stream from the fractionating means, e.g. for re-processing. Thecompacted mass may be put into motion simply by the effect ofgravitation and/or by mechanical means.

A number of fractionating means are known which may be suitable for usein performance of the invention. The fractionating means may for examplecomprise a moving device e.g. a rotating device, such as a cylinder (orcone), along the axis of which the compacted mass is moved in the gasstream. Movement of the compacted mass may be by gravitational means ormay be facilitated by mechanical means, or by features of the device(e.g. cylinder). The rotating device may comprise at least one structurefor guiding the compacted mass inside the rotating device, such as byprovision of a spiral structure. The spiral structure may be formed ofchannels or baffles which guide the movement of the compacted mass. Acomponent of gravitational assistance or resistance may be provided bytilting the axis of the rotating device.

Advantageously the fractionating means does not require passage of thecompacted mass through any sieve (such as a mesh screen). Sieves have atendency to break up lightly compacted granules, therefore avoidance ofuse of a sieve permits lightly compacted granules, with their favorableproperties, to be preserved e.g. for tableting. Moreover sieves areeasily clogged, which disrupts the process, especially when run incontinuous operation. Additionally, the eye size of a sieve may varyduring the period of operation due to transient clogging.

The fractionating means may contain apertures through which fineparticles and/or small granules are entrained. In one specificembodiment of the invention the gas stream enters the rotating devicealong its axis (in the opposite sense to movement of the compacted mass)and exits the rotating device through apertures (perforations) in theside walls of the rotating device.

As noted above, the fractionating means may comprise a moving device,e.g. a rotating device to move the compacted mass in the fractionatingmeans. The moving device may comprise apertures through which the gasstream flows into and out of the moving device and through which thefine particles and/or small granules are entrained. The aperturesthrough which gas flows out of the device may be substantially largerthan rejectable fine particles, e.g. at least 50%, 100% or 150% of theaverage diameter of accepted granules. In absolute terms, the aperturesmay for example have a minimum dimension of around 250 μm, 500 μm or 750μm or more. This helps prevent the apertures from clogging even whenrelatively high volumes of fine particles of possibly sticky materialneed to be separated from the compacted mass. In this sense, the movingdevice significantly differs from an air sieve of the prior art wherethe sieve mesh size must be of about the same size as the largestrejected particle. Instead of relying on the mesh size in the sieving,the fractionating device of the invention relies on the gas stream'sability to entrain fine particles from the moving compacted mass. Thedetermination of the size of acceptable granules is achieved bybalancing their gravitational force (together with other forces, e.g.mechanical and centrifugal forces) against the force of the gas stream.

Some of the fine particles and/or small granules may be agglomerated toother granules in the fractionating means and/or in the pneumaticconveying means by means of the individual or combined influence of thecarrier gas stream, mechanical forces, attractive forces andelectrostatic forces, for example. Thus, the process may producegranules that are larger than what is produced by the flake crushingscreen of the system. In some embodiments, the degree of agglomerationof the compacted mass in the fractionating phase may be significant.

The movement of the mass in the gas stream may be achieved by applying,for example, a mechanical force, gravitational force, centrifugal forceor a combination of these. In some embodiments, a mechanically movingcomponent in the fractionating means may not be needed at all to realizethe benefits of the present invention. In some embodiments, theacceptable granules fall in a gas stream e.g. by effect of gravitationforce and unacceptable particles and granules are moved to at leastpartially opposite direction by the gas stream.

Typically the average residence time of the compacted mass within thefractionating means is at least 2 seconds, perhaps even at least 5seconds, although the desired fractionating effect (including anyagglomerating effect) may be achievable also in a time frame shorterthan that.

It should also be noted that the rejected fraction of the mass may alsocontain acceptable granules. By allowing some recycling of acceptablegranules the overall apparatus may be made e.g. more efficient andeasier to maintain as clogging of fractionating device may be moreeasily avoided. These rejected acceptable granules may be conveyed tothe beginning of the granulating process along with the other rejectedmaterial for reprocessing. For efficiency, we prefer that at maximum 30,45, 60 or 75 percent of acceptable granules are re-cycled with thefines. The inventors have not observed any detrimental effect on thegranulate mass caused by recycling. This is attributable to the use oflow compaction force.

According to a further feature of the invention we provide an apparatuscomprising compacting means and means adapted to separate fine particlesand/or small granules from a compacted mass by entraining the fineparticles and/or small granules in a gas stream, e.g. air.

Thus an apparatus according to the invention may be characterized inthat said fractionating means for example comprising a rotating device(see e.g. (401) in the drawings) comprises at least one exit aperture(see e.g. (511) in the drawings) through which said gas stream flows outof said means said aperture being large enough to allow a granule havingacceptable properties (e.g. flowability, tabletability, size, especiallysize) to flow out of said device.

The apparatus may further comprise a separating means (e.g. a cyclone)to separate the gas stream from the particles removed from the compactedmass.

A further specific aspect of the invention provides an apparatus for drygranulation, characterized in that the apparatus comprises compactingmeans capable of producing low compaction force and fractionating meansadapted to separate fine particles and/or small granules from acompacted mass by entraining the fine particles and/or small granules ina gas stream. The apparatus may suitably comprise a roller compactor togenerate a ribbon of compacted powder which is then broken up to producegranules. Said apparatus may be characterized in that said fractionatingmeans comprises means to move said compacted mass. Said means to movesaid compacted mass may comprise means to move said compacted mass bygravitational or mechanical means. An apparatus according to theinvention may, for example, be characterized in that said fractionatingmeans comprises at least one structure (see e.g. (403) in the drawings)for guiding said compacted mass inside said fractionating means.

An apparatus according to the invention may comprise means to providethe gas stream wherein the direction of the flow of the gas stream has acomponent which is contrary to that of the direction of flow of thecompacted mass (e.g. the direction of the flow of the gas stream issubstantially contrary to that of the direction of flow of the compactedmass).

An apparatus according to the invention is typically provided with afractionating means which comprises a rotating device (e.g. a cylinderor cone, especially a cylinder) along the axis of which the compactedmass is moved in said gas stream. Movement of the compacted mass alongthe axis of the rotating device may be facilitated by means of a spiralstructure which guides the movement of the compacted mass. Thefractionating means e.g. the rotating device may contain aperturesthrough which the fine particles and/or small granules are entrained.When it is desired to produce granules of mean size x, the apertures mayhave a minimum dimension of 0.5×, or 1.0× or even 1.5×. In absoluteterms the apertures may, for example, have a minimum dimension of 250μm, 500 μm or 750 μm.

The invention also provides a fractionating device adapted to separatefine particles and/or small granules from a compacted mass by entrainingthe fine particles in a gas stream which comprises a rotating device,such as a cylinder or cone, along the axis of which the compacted massis moved in said gas stream and which rotating device contains aperturesthrough which fine particles and/or small granules are entrained.

In one embodiment, the fractionating device comprises a fractionatingchamber there being, mounted inside the chamber, an open ended cylinder(or cone). The open ended cylinder (or cone) may be rotatably supportedon rollers. Carrier gas is supplied to the inside of the open endedcylinder (or cone). The jacket of the cylinder (or cone) may beperforated with apertures through which fine particles and/or smallgranules are entrained in the carrier gas. As described elsewhere, theentrained fine particles and/or small granules may be captured forrecycling.

In the method and apparatus according to the invention, pneumatictransport may be used. Suitably, the gas used to entrain the fineparticles in the compacted mass is in fluid communication with thecarrier gas used to transport materials in continuous operation.

Thus, suitably the powder for compaction is conveyed from a reservoir tothe means to apply compaction force by means comprising use of apneumatic conveyor.

The pneumatic transport may use a device, e.g. a cyclone, for separatingcarrier gas from fine particles. The device may be for example capableof continuous operation at an about even gas flow rate, in the sensethat the carrier gas stream used in the fractionating process is notdisturbed by pressure changes, e.g. by pressure shocks, such as arerequired to keep filters of various types open.

“Continuous operation” in this context means ability to operate withoutmaintenance or other interruptions for at least one hour, eight hours or24 hours.

One aspect of the invention is a dry-granulate mass containing granulesobtainable according to the method of the invention.

According to the invention, we also provide a granulate mass, whereinthe granules may have a mean granule size of more than 50, 100, 200 or500 micrometers, maximum granule size of 3, 2 or 1 millimeters and goodflowability. The mass may alternatively or additionally have at leastone, two, three or four of the following properties: substantial absenceof solid bridges between particles within the granule, good homogeneity,porous structure of the granules, substantial proportion of smallgranules and/or fine particles in the mass (typically associated withother granules), good compressibility and tabletability. Suitably thegranules have a mean granule size of more than 100 micrometers and amaximum granule size of 3 millimeters.

Further, without being limited by theory, the inventors believe that theproduct of the process of the invention is influenced by triboelectriceffects caused by passage of powder through the system. It is suggestedin prior art that small particles may have a tendency to develop anegative charge whereas larger particles develop a positive charge (orat least a less negative charge) (see e.g. article “Generation ofbipolar electric fields during industrial handling of powders” by Ion.I. Inculet et al, Chemical Engineering Science 61 (2006), pages2249-2253) e.g. when conveyed by a gas stream or otherwise moved in agas stream. Thus, according to one envisaged embodiment of theinvention, there is provided a dry-granulated granulate mass,characterized in that it contains granules having typically a mean sizeof between 50 μm and 3 mm (e.g. between 100 μm and 3 mm) consisting of(a) a compressed core containing fine particles of material associatedby Van der Waals forces; and (b) a coating layer containing fineparticles and/or small granules of said material associated with saidcompressed core by electrostatic forces. According to another envisagedembodiment of the invention there is provided a dry-granulated granulatemass, characterized in that it contains granules having a mean size ofbetween 50 μm and 3 mm (e.g. between 100 μm and 3 mm) consisting of (a)a compressed core containing fine particles of material associated byVan der Waals forces; and (b) a porous coating layer containing fineparticles and/or small granules of said material. In one embodiment, thecoating layer (b) contains mostly, e.g. 70, 80 or 90%, fine particles asopposed to small granules. In another embodiment, the coating layer (b)contains mostly, e.g. 70, 80 or 90%, small granules as opposed to fineparticles.

Suitably the compressed core is substantially free of solid bridges.

Such a dry granulate mass may also be characterized in that the meanparticle size of the particles of material is 1-100 μm, the mean size ofthe compressed core is 50-3000 μm, and the ratio of the mean particlesize of the fine particles and/or small granules of material of thecoating layer to the mean size of the compressed core is at least 1:10,e.g. at least 1:30.

Most desirable characteristics of the granulate mass are typically goodflowability, good tabletability, good homogeneity, porous structure ofthe granules, substantial proportion of small granules in the mass andsubstantial absence of fine particles in the mass.

To analyze particle size of a granulate mass, a stack of for examplefour sieves may be used where opening sizes of the sieves are forexample 850 μm, 500 μm, 250 μm and 106 μm.

The mean granule size of material accepted by fractionating means may becalculated as the geometric mean of the diameter openings in twoadjacent sieves in the stack.d _(i)=(d _(u) ×d _(o))^(0.5)where

-   -   d_(i)=diameter of i^(th) sieve in the stack    -   d_(u)=diameter opening through which particles will pass (sieve        proceeding i^(th))    -   d_(o)=diameter opening through which particles will not pass        (i^(th) sieve).

Because it is not practical to count each particle individually andcalculate an average, the average particle size can be calculated on aweight basis. This can be done for example with the following equation:d _(gw)=log⁻¹[Σ(W _(i) log d_(i))/ΣW _(i)]^(0.5)

The standard deviation can now be calculated as follows:S _(gw)=log⁻¹ [ΣW _(i)(log d _(i)=log d _(gw))² /ΣW _(i)]^(0.5)

More detailed description of the exemplary size analysis method shownhere is available in an article “Scott Baker and Tim Herrman, EvaluatingParticle Size, Kansas State University, May 2002.”

It should be born in mind that when the particle size of the granulatemass is analyzed by the above method, at least some of the coatingparticles/small granules may be detached from the compressed core.

Flow characteristics, e.g. good flowability, may be determined using anopen-ended cone having a round opening in the narrower end of the cone,e.g. a filter funnel. One set of such cones and related test method isdescribed in more detail with respect to FIG. 9.

Substantial absence of solid bridges in the granule structure means forexample structure where less than 30% or 10% of particles of the granuleare kept together with solid bridges on average. Presence of solidbridges in the granule structure may be analyzed for example using ascanning electron microscope. With such device, it may be possible toidentify individual fine particles in the granulate structure as well asvisible solid bridges such as crystallized structures between theparticles of the granule.

Good homogeneity in this context may mean for example a granulate massthat consists of granules whose standard deviation from mean granulesize is less than 2.5, less than 2.25 or less than 2.0. Inventorsfurther believe that the homogeneous characteristics of the granulatemass of embodiments of the invention may have at least partially beachievable by the porous structure of the granules. Because of thehomogeneous characteristics of the mass, the mass may be conveyed in themanufacturing process without any significant segregation of material.Yet further, good homogeneity of the granular mass may contribute to thegood tabletability of the mass e.g. as demonstrated by lesssusceptibility to the capping phenomenon.

The structure of the accepted granules, and especially a coating layer,may be generally porous, i.e. dense granules may be substantially absentin the granulate mass. The core of the granule is expected to be porousdue to the use of low compaction force. Porous structure of the granulemay alternatively or additionally mean, for example, that the surface ofthe granule may be observed to comprise pores and/or loosely attachedsmall granules and/or fine particles of size of approximately at least1, 2 or 5 micrometers and less than 150, 100 or 50 micrometers. Forexample images about granules having porous structure, see FIGS. 2 d, 2e and 2 f.

Substantial absence of dense granules means that less than 20 or 10percent of the resulting mass weight is dense granules. Dense granule ise.g. a granule whose surface appears to be a compressed, non-porous one(see e.g. FIG. 2 c).

The granulate mass may also comprise a substantial proportion of smallgranules and/or fine particles, possibly forming a coating layer onlarger granules which is loosely attached e.g. via electrostatic forces.A substantial proportion of small granules and/or fine particles may bemore than 2%, 5% or 10% of the overall weight of the granulate mass.Presence of small, preferably porous granules and/or fine particles maycontribute positively e.g. to the flowability and compressibility of thegranulate mass. This may for example lead to an improved tensilestrength and/or more rapid disintegration time of a tablet compressedfrom the granulate mass. Surprisingly, and contrary to what is taught inthe prior art, e.g. in WO99/11261, the substantial proportion of smallgranules and/or fine particles in the granulate mass of the inventiondoes generally not seem to affect the flowability of the granulate massin any significant negative manner.

The inventors have also discovered that, at least in some cases, ifgranules obtained by the process of the invention are taken and aproportion of the starting material composed of fine particles is addedback (e.g. up to 15% fine particles is added back to a granulate massthat may already have e.g. 20% of fine particles and/or small granules,e.g. mass of “flowability example 3”) then the homogeneity, flowabilityand tabletability of the granulate mass is not adversely affected in asignificant manner. The added fines are, perhaps, taken into the poroussurface of granules formed by the process of the invention. Inventorsthus believe that in some embodiments, it may be possible to usegranules of some embodiments of the invention as “carrier granules” thatmay absorb e.g. into the pores of the granules up to 10%, 20%, 30% ormore of fine particles and/or small granules comprising same ordifferent material as the carrier granules. The flowability of suchmixture may be at an excellent, very good or good level.

The granulate mass is believed to have good compressibility because atleast the surface of the granules is porous. The compressibility of thegranulate mass of the invention may be good, i.e. it may have a Hausnerratio of greater than 1.15, 1.20 or 1.25. The low compaction force ofthe present invention may be adjusted so that the compressibility asindicated by the Hausner ratio stays at good level.

The Hausner ratio may be calculated using formula P_(tap)P_(bulk) whereP_(tap) represents tapped bulk density of the granulate mass andP_(bulk) represents the loose bulk density of the granulate mass. Thebulk densities may be measured by pouring 50 mg of granulate mass into aglass cylinder (e.g. make FORTUNA, model 250:2 ml) having an innerdiameter of 3.8 mm. After pouring the mass into the cylinder, the volumeof the mass is observed from the scale of the glass cylinder and loosebulk density of the mass is calculated. To measure the tapped bulkdensity, the glass cylinder is tapped 100 times against a table topusing a force comparable to a drop from the height of 5 cm. The volumeof the tapped mass is observed from the scale of the glass cylinder andtapped bulk density of the mass is calculated.

Surprisingly, and contrary to what is taught in the prior art, e.g. inWO99/11261, the compressibility of the granulate mass of the inventiondoes not generally exhibit any negative influence on the flowability ofthe granulate mass. For example, a granulate mass of an embodiment ofthe invention with Hausner ratio above 1.25 generally exhibits very goodor excellent flow characteristics.

Porous, well-flowing granules are generally desired in thepharmaceutical industry for example because it is possible to produceenhanced tablets from porous granules. Such tablets may for exampledisintegrate substantially quicker than tablets manufactured from densegranules. Further, tablets compressed from porous granules often showhigher tensile strength than tablets compressed from dense granules.High tensile strength is often desirable for tablets as such tablets areeasier to package and transport than fragile tablets.

The granulate mass may be tabletable so that using standard tabletingtechniques, e.g. using tableting forces available in widely usedtableting machines, it is possible to form it into tablets havingtensile strength of at least 5N, 10N or 15N. Tensile strength may bemeasured for example using a measuring device of make MECMESIN™(Mecmesin Limited, West Sussex, UK) and model BFG200N.

The granulate mass may comprise at least one API and/or at least oneexcipient usable in pharmaceutical products. In one embodiment thegranulate mass comprises (e.g. consists of) at least one (e.g. one) API.In another embodiment the granulate mass comprises at least one (e.g.one) API and at least one (e.g. one) excipient.

Thus the invention also provides a process for preparing a tablet whichcomprises compressing a dry-granulated granulate mass according to theinvention optionally blended with one or more additional excipients.Said one or more additional excipients typically comprises a lubricante.g. magnesium stearate. A tablet obtainable by such a process isanother aspect of the invention.

According to the yet further feature of the invention we provide atablet comprising dry-granulated granules. The tablet is characterizedin that the tablet may have substantial absence of solid bridges bindingparticles within the granules forming the tablet. Alternatively orfurther, the tablet may have at least two or three of the followingproperties: high tensile strength, high drug load, low amount oflubricant, quick disintegration time and insensitivity to storage time.

Insensitivity to storage time may mean for example that the weight gainof the tablet in comparison to a new tablet is less than 2.0%, 1.5% or1.0% after the tablet has been stored for four months in temperature of40 degrees Celsius and in the relative humidity of 75%.

High drug load means that, for example the tablet may comprise at least40 percent, 60 percent or 80 percent of API(s) of the overall weight ofthe tablet.

Quick disintegration time may be less than 600, 120 or 30 seconds when atablet is put into water of approximately body temperature (i.e. 37degrees Celsius).

As may be seen from the examples, tablets of the invention which havehigh tensile strength may nevertheless be capable of quickdisintegration in water.

High tensile strength of the tablet may be more than 100N, 60N, 30N or15N, e.g. as measured by MECMESIN™ BFG200N device.

A low amount of lubricant may be less than 1.0%, 0.5%, 0.3% or 0.2% ofthe weight of the tablet. It is known in the art that lubricant materialsuch as magnesium stearate often has detrimental effect on tensilestrength, disintegration time and/or dissolution time of a tablet. Whenmixing lubricant with granules of the prior art, the lubricant materialmay have a tendency to form a film around the (dense) granules, forexample. The film may prevent formation of proper bonds between granulesduring tableting. (See e.g. article “A coherent matrix model for theconsolidation and compaction of an excipient with magnesium stearate” byK. A. Rietma et. al., International Journal of Pharmaceutics, 97 (1993),pages 195-203.) Use of a low amount of lubricant with the granules ofthe present invention may thus contribute positively to the tensilestrength and disintegration time of the tablet. The inventors speculatethat the possibly soft and porous surface of the granule of theinvention may prevent the formation of such films because the granulesmay have a larger, more uneven surface available for the lubricant toassociate with. Thus the properties of the resulting tablet may befurther improved.

The lubricant may be distributed essentially on the porous surface ofthe granules of the tablet. The lubricant may for example be locatedessentially on the surface and in the pores of the surface of thegranules forming the tablet whereas there is no or little lubricantinside the core of the granule. The lubricant may be distributed e.g. sothat more than 90, 80 or 70 percent of lubricant is located in across-sectional area (cut surface) that is less than 10, 20 or 30percent of the total sectional area of a tablet. The location of thelubricant particles on a sectional area of a tablet may be observedusing e.g. a system comprising scanning electron microscope andadditional equipment capable of identifying especially the particlescomprising lubricant material.

The tablet may suitably exhibit substantially low percentage of hydrogenbonding liquid, e.g. water.

A tablet suitably exhibits substantially low percentage of liquid and/orhydrogen bonds, lubricant is unevenly distributed across the tablet andthe tablet has further at least two of the following properties: quickdisintegration time, high tensile strength, high drug load and lowamount of lubricant.

The tablet of the invention may comprise excipient that comprisesdry-granulated starch. For example it may comprise excipient thatcomprises up to 60% of dry-granulated starch.

A granulate mass or tablet of the present invention may typicallycomprise at minimum 1, 5 or 10 percent (weight) and at maximum 100, 95,90, 80 or 70% of at least one active pharmaceutical ingredient. In someembodiments said powder contains an amount of active pharmaceuticalingredient of at least 60% e.g. at least 80%. The granulate mass ortablet may further comprise at minimum 5, 10, 20 or 30% (weight) and atmaximum 99, 95 or 90% of at least one excipient, e.g. long-chain polymere.g. starch or cellulose.

To control the disintegration and dissolution time of a tablet of thepresent invention, up to 90, 70 or 50 percent (weight) of e.g. metholoseor hypromellose (hydroxypropyl methylcellulose) may be added to theformulation. The dissolution time of such tablet may be at least 1, 4, 8or 12 hours in the gastric system.

The dissolution profile of a formulation comprising e.g. hypromellosemay be for example such that after about 2 hours, from about 12% toabout 60% of the API(s) is released; after about 4 hours, from about 25%to about 80% of the API(s) is released; after about 8 hours, from about50% to about 100% of the API(s) is released; after about 12 hours, morethan about 75% of the API(s) is released.

To achieve quick disintegration time for a tablet that comprises atleast 5, 20 or 30 percent (weight) of at least one active pharmaceuticalingredient, the tablet may further comprise at minimum 1, 3 or 5 percentand at maximum 7, 10 or 20 percent (weight) of disintegrant. In someembodiments, the percentage of disintegrant in a tablet may be alsohigher than 20 percent. The disintegrant may be e.g. some starch orcarboxymethyl cellulose (CMC, e.g. Nymcel™) or a combination of these.The granulate mass or tablet may also comprise at minimum 1, 5 or 10percent and at maximum 60, 80 or 94% (weight) of filler (diluent), e.g.microcrystalline cellulose. The API, disintegrant and filler may begranulated together or separately using the method of the presentinvention.

For improving taste of e.g. a fast disintegrating tablet (orallydisintegrating tablet), up to 50, 70 or 90% of sweetener, e.g. xylitolmay be included into the tablet. If necessary, the sweetener may begranulated using an embodiment of the method of present invention.Further, the sweetener may be granulated separately or together with atleast one other component (API or excipient) of a formulation. We haveobserved that at least with some APIs, use of separately granulatedsweetener (xylitol) in a tablet may result as a quicker release time incomparison to a tablet where sweetener is granulated together with othercomponents.

The tablet of the invention may have good content uniformity. Forexample, the standard deviation of the weight of the tablet may be lessthan 3.0%, 2.0% or 1.0% of the average weight of the tablets.

The granulation method and apparatus of the invention can be applied formany purposes in the pharmaceutical, chemical and food industries. Themethod and apparatus use low compaction force and gas stream to formgranules of desired properties. The compaction force may be adjusted sothat introduction of solid bridges is substantially avoided in thecompaction step. The method and apparatus are adapted to treat theproduct granules gently to avoid breaking them, to separate fineparticles and/or small granules from the acceptable granules, andoptionally to re-circulate the rejected material for re-processing inthe system. The apparatus and method can be made easily adjustable,controllable and more or less continuously operable.

The size distribution and/or flowability of the granules produced by theapparatus may be analyzed in real-time and the size distribution of thegranules may be adjusted based on the analysis. For example, the flakecrushing screen (see FIGS. 1 a and 1 b below) may be such that theaperture size of the mesh used for flake crushing can be varied by usingsome adjustment means. Another adjustable parameter typically is the gasflow rate of the fractionating device.

The method can be made economic as it allows re-processing of rejectedmaterial with practically no waste, and can be adapted to provide fasttreatment of large amounts of material. The apparatus of the presentinvention may be adapted to be easy to clean and assemble and theprocess may be adapted to be stable and predictable thus making it easyto control.

Because of, for example, the homogeneity and/or flowability of theresulting granules, issues related to segregation can be avoided. Themethod of the present invention can be used in both small and largescale applications. Thus, when a product, e.g. granules or a tabletcontaining API(s) has been successfully developed under laboratoryconditions, the time required to set up a validated large-scalemanufacturing process can be short.

Because the method and apparatus of the present system is capable ofgranulating a variety of powders, including those consisting of 100%APIs, it is possible to produce granulate mass from separate substancesin separate granulation processes and mix the resulting granulestogether after their individual granulations. Granulating API andexcipients separately before blending may be advantageous e.g. when rawmaterials have very different particle sizes.

Different kinds of end products, including tablets, oral suspensions andcapsules may be manufactured from the granulate mass.

According to the invention, we also provide a process for manufacture ofa tablet which comprises tableting a granule according to the invention,or a granule made using the method of the invention.

We have found that the method of the present invention may be used forproducing granules of large variety of powder substances usable inpharmaceutical industry.

The method of the present invention may thus be applicable to producinggranules and tablets of the invention from material comprising APIs ofone or multiple classes of APIs, the classes including for exampleantipyretics, analgesics, antiphlogistics, hypnosedatives,antihypnotics, antacids, digestion aids, cardiotonics, antiarrhythmics,antihypertensives, vasodilators, diuretics, antiulcers, antiflatulents,therapeutic agents for osteoporosis, antitussives, expectorants,antiasthmatics, antifungals, micturition improvers, revitalizers,vitamins and other orally administered agents. APIs can be used singlyor two or more of them can be used in combination.

The method of the present invention may also be applicable to producinggranules and tablets of the invention from material comprising specificAPIs, for example paracetamol, acebutolol, metformin, fluoxetine,aspirin, aspirin aluminum, acetaminophen, ethenzamide, sazapirin,salicylamide, lactyl phenetidine, isothipendyl, diphenylpyraline,diphenhydramine, difeterol, triprolidine, tripelennamine, thonzylamine,fenethazine, methdilazine, diphenhydramine salicylate, carbinoxaminediphenyldisulfonate, alimemazine tartrate, diphenhydramine tannate,diphenylpyraline teoclate, mebhydrolin napadisylate, promethazinemethylene disalicylate, carbinoxamine maleate, chlorophenylaminedl-maleate, chlorophenylamine d-maleate, difeterol phosphate,alloclamide, cloperastine, pentoxyverine (carbetapentane), tipepidine,dextromethorphan hydrobromide, dextromethorphan phenolphthalinate,tipepidine hibenzate, cloperastine fendizoate, codeine phosphate,dihydrocodeine phosphate, noscapine, dl-methylephedrine saccharin salt,potassium guaiacolsulfonate, guaifenesin, caffeine, anhydrous caffeine,vitamin B1 and derivatives thereof, vitamin B2 and derivatives thereof,vitamin C and derivatives thereof, hesperidin and derivatives thereofand salts thereof, vitamin B6 and derivatives thereof and, nicotinamide,calcium pantothenate, aminoacetate, magnesium silicate, syntheticaluminum silicate, synthetic hydrotalcite, magnesium oxide, aluminumglycinate, coprecipitation product of aluminum hydroxide/hydrogencarbonate, coprecipitation product of aluminum hydroxide/calciumcarbonate/magnesium carbonate, coprecipitation product of magnesiumhydroxide/potassium aluminum sulfate, magnesium carbonate, magnesiumaluminometasilicate, ranitidine, cimetidine, famotidine, naproxen,diclofenac, piroxicam, azulene, indometacin, ketoprofen, ibuprofen,difenidol, promethazine, meclizine, dimenhydrinate, fenethazine tannate,diphenhydramine fumarate, scopolamine hydrobromide, oxyphencyclimine,dicyclomine, metixene, atropine methylbromide, anisotropinemethylbromide, scopolamine methylbromide, methylbenactyzium bromide,belladonna extract, isopropamide iodide, papaverine, aminobenzoic acid,cesium oxalate, aminophylline, diprophylline, theophylline, isosorbidedinitrate, ephedrine, cefalexin, ampicillin, sucralfate,allylisopropylacetylurea, bromovalerylurea, and where appropriate(other) pharmaceutically acceptable acid or base addition salts thereof(e.g. those salts which are in common usage) and other suchpharmaceutically active ingredients described in European Pharmacopoeia,3^(rd) Edition and one, two or more of them in combination.

The method of the present invention may also be applicable to producinggranules and tablets of the invention from material comprising solidAPIs that may be poorly water-soluble, such as for example antipyreticanalgesic agents such as benzoic acid, quinine, calcium gluconate,dimercaprol, sulfamine, theobromine, riboflavin, mephenesin,phenobarbital, thioacetazone, quercetin, rutin, salicylic acid,pyrabital, irgapyrin, digitoxin, griseofulvin, phenacetin, nervoussystem drug, sedation narcotics, muscle relaxant, hypotensive agent,antihistamines, antibiotics such as acetylspiramycin, erythromycin,kitasamycin, chloramphenicol, nystatin, colistin sulfate, steroidhormones such as methyltestosterone, progesterone, estradiol benzoate,ethinylestradiol, deoxycorticosterone acetate, cortisone acetate,hydrocortisone, prednisolone, non-steroid yolk hormones such asdienestrol, diethylstilbestrol, chlorotrianisene, other lipid solublevitamins, and where appropriate (other) pharmaceutically acceptable acidor base addition salts thereof (e.g. those salts which are in commonusage) and other such pharmaceutically active ingredients described inEuropean Pharmacopoeia, 3^(rd) Edition and one, two or more of them incombination.

The active pharmaceutical ingredient may, for example, be selected fromacebutolol HCl, fluoxetine HCl, paracetamol, sodium valproate,ketoprofen and metformin HCl.

The method of the present invention may also be applicable to producinggranules and tablets of the invention from material comprisingexcipients or other ingredients usable in e.g. pharmaceutical industry,such as for example L-asparagic acid, wheat gluten powder, acaciapowder, alginic acid, alginate, alfa-starch, ethyl cellulose, casein,fructose, dry yeast, dried aluminum hydroxide gel, agar, xylitol, citricacid, glycerin, sodium gluconate, L-glutamine, clay, croscarmellosesodium, Nymcel™, sodium carboxymethyl cellulose, crospovidone, calciumsilicate, cinnamon powder, crystalline cellulose-carmellose sodium,synthetic aluminum silicate, wheat starch, rice starch, potassiumacetate, cellulose acetate phthalate, dihydroxyaluminum aminoacetate,2,6-dibutyl-4-methylphenol, dimethylpolysiloxane, tartaric acid,potassium hydrogen tartrate, magnesium hydroxide, calcium stearate,magnesium stearate, purified shellac, purified sucrose, D-sorbitol, skimmilk powder, talc, low substitution degree hydroxypropylcellulose,dextrin, powdered tragacanth, calcium lactate, lactose, sucrose, potatostarch, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate,glucose, partially pregelatinized starch, pullulan, powdered cellulose,pectin, polyvinylpyrrolidone, maltitol, maltose, D-mannitol, anhydrouslactose, anhydrous calcium hydrogenphosphate, anhydrous calciumphosphate, magnesium aluminometasilicate, methyl cellulose, aluminummonostearate, glyceryl monostearate, sorbitan monostearate, medicinalcarbon, granular corn starch, dl-malic acid and possibly other suchothers classified as excipient in Arthur H. Kibbe: Handbook ofPharmaceutical Excipients, 3^(rd) Edition, and one, two or more of themin combination.

The method of the present invention may be applicable to producinggranules and tablets of the invention from material comprisingdisintegrants such as for example carboxymethyl cellulose, Nymcel™,sodium carboxymethyl cellulose, croscarmellose sodium, cellulose such aslow substitution degree hydroxypropylcellulose, starch such as sodiumcarboxymethyl starch, hydroxypropyl starch, rice starch, wheat starch,potato starch, maize starch, partly pregelatinized starch and othersclassified as disintegrators in Arthur H. Kibbe: Handbook ofPharmaceutical Excipients, 3^(rd) Edition, and one, two or more of themin combination.

The method of the present invention may be applicable to producinggranules and tablets of the invention from material comprising binderssuch as for example synthetic polymers such as crospovidone, saccharidessuch as sucrose, glucose, lactose and fructose, sugar alcohols such asmannitol, xylitol, maltitol, erythritol, sorbitol, water-solublepolysaccharides such as celluloses such as crystalline cellulose,microcrystalline cellulose, powdered cellulose, hydroxypropylcelluloseand methyl cellulose, starches, synthetic polymers such aspolyvinylpyrrolidone, inorganic compounds such as calcium carbonate andothers classified as binders in Arthur H. Kibbe: Handbook ofPharmaceutical Excipients, 3^(rd) Edition, and one, two or more of themin combination.

Examples of fluidizing agents include silicon compounds such as silicondioxide hydrate, light silicic anhydride and others classified asfluidizing agents in Arthur H. Kibbe: Handbook of PharmaceuticalExcipients, 3^(rd) Edition, and one, two or more of them in combination.

According to another aspect of the invention, we provide a granulatemass, characterized in that the mass is tabletable and has goodflowability and that the mass comprises at least 10% of at least one ofthe following pharmaceutical ingredients:

-   -   acebutolol HCl,    -   fluoxetine HCl,    -   paracetamol,    -   sodium valproate,    -   ketoprofen and    -   metformin HCl.

According to another aspect of the invention, we provide a tablet,characterized in that the tensile strength of the tablet is at least 10Nand the tablet is manufactured from dry-granulated granules comprisingat least 10% (weight) of at least one of the following activepharmaceutical ingredients:

-   -   acebutolol HCl,    -   fluoxetine HCl,    -   paracetamol,    -   sodium valproate,    -   ketoprofen, and    -   metformin HCl.

According to another aspect of the invention, we provide a tablet formedby compression of a dry granulate mass comprising 60% or more (e.g. 70%or 80% or more) of active pharmaceutical ingredient selected fromparacetamol, metformin HCl, acebutolol HCl and sodium valproate. Thebalance of the composition of the dry granulate mass may, for example beone or more disintegrants selected from starch, cellulose and cellulosederivatives. According to another aspect of the invention, we provide atablet formed by compression of a dry granulate mass comprising (i)granules comprising 80% or more (e.g. 90% or more e.g. 100%) of activepharmaceutical ingredient selected from paracetamol, metformin HCl,acebutolol HCl and sodium valproate and (ii) granules comprising one ormore disintegrants selected from starch, cellulose and cellulosederivatives. In either case a lubricant may optionally be blended withthe dry granulate mass before compressing it into tablets.

In some embodiments, the tablets disintegrate in water of approximatelybody temperature, i.e. 37 degrees Celsius, in less than 60 seconds. Forquick disintegrating tablets, the API suitably does not exceed 95% ofthe tablet composition and the composition contains at least 2% ofdisintegrant. The tablets suitably have a tensile strength of greaterthan 40N. In one embodiment the tablets may comprise xylitol in anamount of 90% or less.

Some embodiments of the invention are described herein, and furtherapplications and adaptations of the invention will be apparent to thoseof ordinary skill in the art.

BRIEF DESCRIPTION OF DRAWINGS

In the following, the invention is illustrated, but in no way limited byreference to the accompanying drawings in which

FIG. 1 a and FIG. 1 b show exemplary apparatus according to anembodiment of the invention,

FIG. 2 a shows use of roller compactor according to an embodiment of theinvention,

FIG. 2 b shows use of roller compactor producing both avoidable dense(according to prior art) and desirable porous granules,

FIG. 2 c shows an example of a granule produced by a method of priorart.

FIG. 2 d shows an example of a granule according to an embodiment of theinvention.

FIG. 2 e shows another example of granules according to an embodiment ofthe invention,

FIG. 2 f shows yet another example of granules according to anembodiment of the invention,

FIG. 2 g illustrates an example about formation of granular mass of anembodiment of the present invention,

FIG. 2 h shows particle size distribution diagrams of materials shown inFIG. 2 g,

FIG. 2 i shows surface images of granules produced using different lowcompaction forces according to embodiments of the present invention,

FIG. 3 shows an exemplary fractionating device according to anembodiment of the invention,

FIG. 4 shows an exemplary fractionating device that contains anadditional rotating device usable according to an embodiment of theinvention,

FIG. 5 a and FIG. 5 b show two alternative exemplary cylindricalcomponents that can be used in the fractionating device shown in FIG. 4,

FIG. 5 c shows an exemplary perforated steel sheet that may be used aspart of a rotating device according to an embodiment of the presentinvention,

FIG. 6 shows an exemplary dual-filter arrangement for enablingcontinuous operation of the system of an embodiment of the presentinvention,

FIG. 7 shows an exemplary arrangement for monitoring and adjusting thecharacteristics of the accepted granules in real time,

FIG. 8 shows an exemplary arrangement for mixing granulate masses fromseparately compacted substances, and

FIG. 9 shows an exemplary device for determining flowability of a powderor granulate mass.

DETAILED DESCRIPTION OF DRAWINGS

The apparatus 100 (FIGS. 1 a and 1 b) of an embodiment of the inventioncomprises a compacting device that compacts powder material intogranules and a fractionating device that fractionates at least some fineparticles and/or small granules away from acceptable granules. Twodifferent alternatives for a fractionating device are shown in FIGS. 1 aand 1 b. The fractionating device 112 in FIG. 1 a is shown in moredetail in FIG. 3. The fractionating device 112 in FIG. 1 b is shown inmore detail in FIG. 4. The apparatus shown in FIG. 1 a and FIG. 1 bcomprise a raw material feeding container 101, into which material to begranulated is fed. The feeding container is connected to a pneumaticconveyor pipeline 102, to which the material is passed through a feedervalve 103. The tubes of the pneumatic conveyor system have a diameter ofabout 47 mm and their material may be for example some suitable plasticmaterial, e.g. polyethene. The feeder valve may be a so-calledstar-shape flap valve. One such valve is manufactured by Italianpharmaceutical device manufacturer CO.RA™ (Lucca, Italy). In operation,the closing element of the valve may be turned 180° alternately ineither direction, whereby buildup of the powder substance in thecontainer can be avoided. Other equipment intended for continuouscharging of powder substance, such as compartment feeders, may also beused.

The pressure of the air flowing within the conveyor 102 may be adjustedto be lower than that of the surroundings. This may be achieved forexample using an extractor suction fan 104. The suction fan is of makeBUSCH™ (Maulburg, Germany) and model Mink MM 1202 AV. The fan may beoperated for example at 1860 RPM. Makeup carrier gas may be suppliedthrough a connection 105. The material fed from the feeding container istransported through the conveyor 102 into a separating device 106,wherein fine rejected particles and new feed from container 101 areseparated from the carrier gas. The fan can be provided with filters(shown in FIG. 6) situated beside the separating device. The device maybe capable of continuous operation. One such device is a cyclone. Afterthe separating step, the separated powder falls into an intermediatevessel 107.

The container 107 can be mounted on load cells 108 to measure the weightof the material. The intermediate vessel 107 is provided with a valve109 which may be of the same type as the feeding container valve 103.From the intermediate vessel 107, the powder is transferred to acompacting device, e.g. roller compactor 110 to produce a ribbon ofcompacted material which is then passed to a flake crushing screen 111where granules are created by crushing the ribbon. In the context ofthis invention, compacting is considered as the step of the process thatproduces granules to be fractionated, regardless of whether a separatescreen or milling device 111 is used or not. The compaction force of thecompactor 110 may be adjusted by e.g. altering the feed rate of thepowder substance, the rotating speed of the rolls of the rollercompactor, the pressure applied to the rolls of the compactor deviceand/or the thickness of the resulting ribbon. The compaction forceapplied by the compactor may be adjusted to a low level to achieve thedesired properties of the compacted mass, e.g. the porosity of theresulting granules and/or proportion of fine particles and/or smallgranules. The compactor and the flake crushing screen are devices wellknown to a person skilled in the art. After passing the compacting andflake crushing devices, the material is partially in the form ofgranules, but part of the material will still be in the form of fineparticles and/or small granules. The maximum size of the granules aswell as the mean size of the granules may be affected by, for example,the mesh size of the flake crushing screen. It should be noted, however,that size of a granule may increase as result of agglomeration in thefractionating and/or conveying steps of the process.

In some embodiments (not shown in figure), the apparatus 100 maycomprise more than one compacting device, e.g. roller compactor, toimprove e.g. capacity and/or continuous processing capabilities of theapparatus. The compacting devices may require some periodic servicebreaks e.g. for cleaning up. The apparatus 100 may continue operationeven if one of the compacting devices is being serviced.

The product from the above steps that contains fine particles and porousgranules and that may be statically charged (e.g. bytriboelectrification) is conveyed to a fractionating chamber 112. Theremay be one or two e.g. star-shaped flap valves between compacting deviceand fractionating device to control the flow of compacted material tothe fractionating device. The fractionating device divides the granulatemass into an accepted fraction and a rejected fraction on the basis ofhow different particles of the mass are affected by the carrier gasstream that flows in the fractionating device. The rejected fractionpasses with the fed carrier gas stream to the feed conveyor 102, forre-processing, and the accepted fraction is led into a product container113. By this means the product granules are treated gently and arelatively large volume of material comprising mostly fine particlesand/or small granules is removed from the mass.

The operation of the fractionating chamber 112 is described in moredetail with reference to FIGS. 3-6. There are many possible alternativefractionating devices.

In the embodiments shown in FIG. 1 a and FIG. 1 b, load cells 108 arefitted to the container 107. Such sensors and other instrumentation canalso be arranged in other containers and components of the system. Notall of the possible instrumentation is shown in the figures. For examplethe pneumatic conveyor, if required, may be provided with at least onepressure difference sensor 114, the information from which can be usedto control the operation of the apparatus.

The present invention may also be carried out as a batch process wherethe reject fraction is not immediately returned to the system using theconveyor 102, but fed into a container of reject material. Such a systemis not described in detail, but its construction and use will be readilyapparent to those of skilled in the art.

The apparatus can be automated by transferring information received fromthe various sensors e.g. the pressure difference sensors 114, the loadcells 108 and the valves 103 as well as information regarding the speedof rotation and the loads of the motors to a control unit and byapplying appropriate control logic and control circuits in a mannerknown to a person skilled in the art. Control of the compaction force ofthe compacting device, e.g. roller compactor is particularly useful, asgranule structure as well as the proportion of fine particles and/orsmall granules is significantly affected by the compaction force used.The compaction force depends on a number of parameters, such as therotating speed of the rolls and the feed rate of the powder substance.For example, the higher the feed rate of the powder substance for agiven roller rotation rate, the higher the compaction force will be.

The material of the conveyor 102 may be e.g. PVC, e.g. FDA PVC. Variouscomponents of the system may be connected together with electric wiresfor grounding purposes. Suitably the entire system is grounded.

In FIG. 2 a the roller compactor 200 compacts the mass 203 containingraw material and optionally particles recycled from the fractionatingdevice into a ribbon 204, 205, 206 using rolls 201,202 that applymechanical force to the mass to be compacted. Depending on thecompaction force applied to the mass and the thickness of the ribbon,the amount of mass that gets compacted into granules 204, 205 varies.The remaining mass 206 may remain small granules and/or fine particlesexample in the middle of the ribbon. The small granules and/or fineparticles may not be capable of forming acceptable granules alone.However, the presence of such mass may have a positively contributingrole in forming of acceptable granules in the fractionating and/orconveying steps of the process e.g. through triboelectrification andelectrostatic forces. Depending on the feed material and compactingparameters, such as thickness of the ribbon, the proportion of fineparticles and/or small granules may vary.

A convenient way to adjust operating parameters of the system is to setthe compaction force of the roller compactor to the minimum thatproduces at least some granules and set the rotating speed (see thedescription related to FIG. 4) of the fractionating device to themaximum available (e.g. about 100 RPM) in the device of make ROTAB™(Donsmark Process Technology A/S, Copenhagen, Denmark) and model400EC/200 and then adjust the carrier gas flow rate so that acceptablegranules with desired flow characteristics start flowing out the system.Too little gas flow in the fractionating device causes the proportion offine particles and/or small granules to increase in the mass of acceptedgranules whereas use of too high a gas flow causes a large proportion ofacceptable granules to be unnecessarily re-processed. Setup of theoptimal gas flow may be done manually or automatically for example usingreal-time measurement of flow of accepted granules and characteristicsof those granules. One such measurement arrangement is shown in FIG. 7.

FIG. 2 b illustrates an example of the creation of unwanted densegranules and/or granules having solid bridges 210, 211 when a highcompaction force as in the prior art is used. The more dense granulesthere are in the mass, the lower the quality of the mass may be fortableting. Although the flow characteristics of the mass resulting fromusing prior art high compaction forces (or repeated compaction withlower forces) may be acceptable even without fractionating, thecompressibility and/or tabletability of the mass may with some materialsbe significantly lower, or some other characteristics of the tablet suchas disintegration time may be undesirable. Moreover, significant heatingof the material in the compaction step of prior art granulation processmay be observed leading for example to formation of solid bridgesthrough crystallization and/or degradation of components of the granulesor undesirable characteristics of the granulate mass. Yet further, useof high compaction force typically reduces the proportion of smallgranules and/or fine particles 206 in the resulting granulate mass. Toolow a percentage of such small granules and/or fine particles in thefractionating and/or conveying steps of the process may adversely affectthe quality of the resulting accepted granules.

FIG. 2 c shows a scanning electronic microscope (SEM) picture of anexemplary dense maize starch granule that is produced using highcompaction force (e.g. more than 80 kN using Hosokawa Bepex PharmapaktorL200/50P roll compactor) for maize starch (CERESTAR™ product code C*Gel03401, batch number SB4944) typical of the dry granulation methods ofthe prior art.

FIG. 2 d shows a picture of an exemplary porous starch granule of thesame starch that is produced using low compaction force (in this case,30-35 kN using the same Hosokawa roll compactor) and subsequentfractionation using gas stream according to an embodiment of the presentinvention. For different materials, the “low compaction force” thatproduces porous granules and “high compaction force” that producesunacceptable amount of dense granules and/or granules with solid bridgesmay vary. We have observed that the surface of the granule of FIG. 2 cis less porous (i.e. more dense) than the granule of FIG. 2 d. There ismore free space (i.e. pores) between the individual particles in theporous granule of FIG. 2 d than in the dense granule of FIG. 2 c. Therealso seems to be larger proportion of loosely attached particles on thesurface of the porous granule of FIG. 2 d than in the dense granule ofFIG. 2 d. Further, the granule of FIG. 2 c has more edges than thegranule of FIG. 2 d. The round shape of the porous granule maycontribute to the good flow characteristics of the granulate masscontaining such granules. The pores between particles on the surface ofthe porous granule as shown in FIG. 2 d may enhance the compressibilityof the granule.

FIG. 2 e shows another embodiment of granules of the present invention.Image 250 shows a plurality of 100% paracetamol granules 251 produced bythe apparatus of an embodiment of the invention. Compaction force of 60kN was used in the granulation process. According to our observation,paracetamol may be granulated using higher compaction forces than mostother materials. Unless specified differently, the fractionating deviceused in the process of this and following examples is similar to the onedescribed in FIGS. 4 and 5 c. Typical size of a granule 251 in thissample is between 500 and 1000 μm. Image 252 shows a magnified pictureof the surface of one of such granules. It may be observed from image252 that the compacted surface 254 of the granule is covered mostly bysmall granules 255 (e.g. in the range of ca 5 μm-50 μm). Such individualsmall granules 257 are also shown in image 256. The small granules 255are relatively loosely attached to the granule 251 forming a poroussurface for the granule. Thus, although the compaction force used washigher than with typical materials, the surface of the resultinggranules can be visually observed to be porous. Inventors contemplatethat the small granules and/or fine particles may have been attached tothe larger granules via electrostatic forces created e.g. bytriboelectrification during the fractionating step of the process. Theinventors contemplate further that the porous surface achieved vialoosely attached small granules on the surface of the accepted granulemay have a significant positive contribution to the flow andtabletability properties of the granulate mass.

FIG. 2 f shows yet another embodiment of granules of the presentinvention. Image 260 shows a plurality of excipient granules 261comprising 70% of microcrystalline cellulose and 30% of maize starch. Acompaction force of 16 kN was used in the granulation process. Typicalsize of a granule 261 in this sample is between 500 and 1000 μm. Image262 shows a magnified picture of the surface of one of such granules. Itmay be observed from image 262 that the compacted surface of the granuleis covered by small granules and/or fine particles 263 (e.g. in therange of ca 5 μm-100 μm). Such individual small granules 265 andindividual fine particles 266 are also shown in image 264. Smallgranules 265 and fine particles 266 are relatively loosely attached tothe granule 261 forming a porous surface for the granule. The proportionof small granules (in this example, granules smaller than 106 μm) wasapproximately 20%. The flowability of the mass was observed to beexcellent.

FIG. 2 g illustrates formation of granules from raw material comprising50% microcrystalline cellulose and 50% of maize starch. Image 270 showsa SEM-image of unprocessed raw material. Image 271 shows a SEM-image ofcompacted but not yet fractionated granular mass. Compaction force of 25kN was used in the experiment. Image 272 shows a SEM-image of granularmass accepted by the fractionating device of an embodiment of thepresent invention. The magnification of images 270 and 271 isessentially similar and image 272 has 0.1× magnification in comparisonto images 270 and 271. Image 270 shows practically no granules. In image271, attention is drawn to the relatively small size of the granulesproduced in the compacting step. Granules in the compacted mass 271created by the roller compactor and flake crusher (110 and 111 in FIGS.1 a and 1 b) are generally smaller than 500 μm whereas majority of thegranules 272 accepted by the fractionating device (see FIG. 4) arelarger than 500 μm. This surprising observation makes inventors believethat new acceptable granules may be created and/or granules may furtheragglomerate during the fractionating phase of the method of anembodiment of the present invention.

FIG. 2 h shows particle size distribution charts of materials depictedin images 271 and 272 of FIG. 2 g. According to the productcertification data of raw materials used, the size distribution ofparticles of the raw material (not shown in figures) is such thatpractically all particles of the mass are smaller than 106 μm. When themass is compacted, the proportion of granules of acceptable sizeincreases slightly as shown in image 280 but the majority (approximately73%) of particles are still smaller than 106 μm. Image 281 shows thatafter fractionation, the proportion of granules larger than 106 μmincreases significantly. The accepted fraction still contains about 10%of small granules and/or fine particles smaller than 106 μm. Despite therelatively large proportion of small granules and/or fine particles, themass exhibits excellent flowability. The total proportion of granulesaccepted from the compacted mass in the fractionating step wasapproximately 10%. Thus, approximately 90% of the mass was rejected bythe fractionating device.

FIG. 2 i shows SEM-images of surfaces of granules manufactured usingembodiments of the present invention. Different compaction forces havebeen used in the granulating process. The material shown comprises 50%of microcrystalline cellulose and 50% of maize starch. Images 290, 291,292 depict granules produced using compaction force of 25 kN, 40 kN and60 kN, respectively. Attention is drawn to the decreasing surfaceporosity when the compaction force is increased. Numerous pores areeasily detectable in granules of images 290 and 291 whereas there arelarge dense areas in granule of image 292. Lack of pores on the surfaceof the granule may deteriorate at least some of the properties of thegranular mass, e.g. flowability of the mass, tabletability of the massand/or disintegration time of resulting tablet. Thus it is suggestedthat the optimal compaction force for producing granules from this rawmaterial is probably below 60 kN. Although the SEM images 290, 291 don'tshow significant differences in the structure of the surface of thegranule, the granular mass produced using compaction force of 25 kN formtablets with higher tensile strength and quicker disintegration timethan the mass produced with compaction force of 40 kN.

FIG. 3 shows an exemplary fractionating device for removing fineparticles and/or small granules from the granulate mass 303 produced bythe compactor. The device has a chamber 300 that contains apertures fordifferent purposes. Input material 301 from the compactor and flakecrusher is fed through one or multiple apertures 302. Gravity makes thematerial 305 flow downwards towards aperture 304 through which theaccepted granulate mass 306 flows out of the system into a container.From the same aperture 304, carrier gas (air) 307 flows into the system.The gas may flow into the system also from some other aperture that ispositioned such that the desired fine particle and/or small granulesremoving effect of the carrier gas flow is achieved. The carrier gasflows in a direction that is different from (countercurrent to) the flowof accepted granules. Accepted granules fall out of the fractionatingdevice through tube 304 by effect of gravitation. While the granules aremoving in the fractionating device 300, fine particles and/or smallgranules may agglomerate with other granules, thus making the granulesgrow further. The fine particles and/or small granules 308 are carriedaway from the fractionating device by the carrier gas flow 309 throughaperture 310. There may be multiple apertures for the accepted granulesas well as for the rejected fine particles and/or small granules.

FIG. 4 illustrates an example of an enhanced fractionating device. Inthe figure, components and structures residing inside the device aredrawn using dotted lines. The device 400 comprises a fractionatingchamber and, mounted inside the chamber, an open ended cylinder (orcone-shaped device, not illustrated) 401 rotatably supported on rollers410. The rotating speed of the cylinder can be adjusted to be forexample the maximum available in the device of make ROTAB™ (DonsmarkProcess Technology A/S, Copenhagen, Denmark) and model 400EC/200. Thejacket of the cylinder or cone may be perforated. There are norestrictions with regard to the number and shape of the possibleapertures or their edges except for that the apertures should beconstructed so that the gas (air) together with entrained fine particlesis able to leave the cylinder through them. The apertures may be, forinstance, round, oval or slots. In one embodiment, the apertures areround and they have been cut using laser cutting techniques. In oneembodiment, the diameter of the round apertures is 1.5 mm. A drive motor402 is arranged to rotate the cylinder at a suitable speed, e.g. at 100RPM. A spiral structure 403 is provided inside the cylinder fortransporting the solid material from the feed end 411 to the outlet 404as the cylinder rotates. Instead of a spiral, various kinds of fins orother structures can be provided internally within the cylinder toobtain movement of the compacted material, and its interaction with thegas stream. The angle of inclination of the cylinder may be adjusted asrequired by, for instance, changing the position of the wholefractionating device 400 in its suspension structure 413, 414.

The powder 405 leaving the compacting device falls through a chargeconnection 412 into the feed end 411 of the cylinder and is transportedby the spiral 403 towards an outlet tube 404. The carrier gas 406flowing through the outlet 404 moves in the opposite direction to theaccepted granules 407. Acceptable granules pass along in the cylinder401, and fall through the outlet 404 to a product container (not shown)by effect of gravitation. Unacceptable fine particles and/or smallgranules that may be accompanying the acceptable granules to the tube404 are generally conveyed back from the tube 404 to the cylinder 401 bythe gas stream 406. In the present device, the outlet 404 is a downwardpointing tube whose length is 70 mm and diameter is 40 mm. The rejectedfraction of fine particles and/or small granules 408 together with thecarrier gas stream flows to the feeding conveyor (see 102 in FIG. 1),through connection 409 for reprocessing. The granules may grow in sizein the fractionating device 400 (or 300 in FIG. 3). This agglomerationmay be caused e.g. by triboelectrification and electrostatic forces.

The properties of the accepted fraction may be influenced e.g. bychanging the rotation speed of the cylinder, the angle of inclination ofthe cylinder, the pitch of the spiral, and the size, number and locationand the shape of the apertures in the cylinder as well as by varying theflow rate of the carrier gas.

FIGS. 5 a and 5 b show two different forms of the cylinder-shaped deviceresiding inside the fractionating device (see 400 in FIG. 4). A cylinder500 has apertures 501 that in the FIG. 5 a are situated throughout thejacket of the cylinder whereas in FIG. 5 b there are apertures only inone end of the cylinder. The input material 502 that contains bothgranules and fine particles is fed to the rotating cylinder from one endof the cylinder. The rotating movement 503 of the cylinder 500 and thespiral (see 403 in FIG. 4) inside the cylinder push the input materialtowards the other end of the cylinder. While the material is moving inthe cylinder, carrier gas flow 504 separates the acceptable granulesfrom the rejected fine particles and/or small granules 505 which areconveyed out of the cylinder through apertures 501 with the carrier gasflow. The accepted granules 506 are eventually pushed out of thecylinder by the spiral structure that resides inside the cylinder.

In the shown embodiment, the rotating device is a cylinder of diameterof 190 mm and length of 516 mm and comprises apertures each having adiameter of 1.5 mm and the apertures reside on average 6 mm from eachother. The air stream that enters the fractionating device throughaperture 404 (FIG. 4) is further led out of the fractioning chamber forreprocessing through an aperture (409 in FIG. 4) of 50 mm in diameter.Inside the cylinder there is a screw-shaped guiding structure thatadvances 80 mm per revolution towards the aperture of accepted material506. The height of the guiding structure is 25 millimeters. FIG. 5 cshows a drawing of an exemplary perforated stainless steel sheet thatmay be used to build a suitable cylinder. The thickness of the sheet isabout 0.8 mm. The ROTAB™ device described above has been modified bychanging the cylinder to one assembled from the steel sheet of FIG. 5 cand the fractionating chamber has been changed to one having the shapesimilar to one shown in 400 of FIG. 4.

Although the devices shown in FIGS. 5 a and 5 b are open-ended andcylinder shaped, and the movement involved is a rotating movement,conveyor devices of other shapes and utilizing other kinds of movementsmay also be used to convey the mass in the fractionating air stream.

The device may optionally be adapted to improve its continuousprocessing capabilities. One such adaptation is disclosed in FIG. 6where a dual filter assembly is illustrated. The majority of fineparticles and/or small granules is separated from carrier gas, e.g. air,in cyclone 602 (see also 106 in FIG. 1 a or 1 b), but some fineparticles and/or small granules may be sucked out of the cyclone withthe carrier gas. Those particles may need to be filtered out before thecarrier gas leaves the system. The filters 607 a, 607 b collect the fineparticles and/or small granules until the filter is cleaned. One filter607 a, 607 b may be active while the other is being cleaned e.g. byvibrating it. The valves 605, 612 may be used for guiding the gas flowthrough the active filter and for isolating the filter being cleanedfrom the gas stream. The powder resulting from the filter cleaning fallsbelow the filter and further to a tube 609 a, 609 b when the valve 608a, 608 b respectively is opened. In the other end of the tube, there maybe a lower valve 610 a, 610 b that is opened after the upper valve 608a, 608 b has been closed. Opening the lower valve causes the powder tofall back into the circulation for re-processing. This arrangement makesit possible to clean one of the filters while the apparatus isoperational and the cleaning operation doesn't result in undesirablepressure shocks of carrier gas in the apparatus.

The apparatus may also optionally be equipped for example with sensorsthat measure the size of accepted granules in real-time. Such anarrangement is shown in FIG. 7. Accepted granules leave thefractionating device 700 through tube 701. Light emitting devices 702 aswell as light sensitive sensors 703 have been installed in the tube toobserve the size of the passing accepted granules. Based on theinformation created by the sensors, the control logic of the system mayadjust the operating parameters of the apparatus. One such adjustableparameter may be for example the size of granules produced by the flakecrushing screen 704. Another such adjustable parameter may be the gasflow rate of the system.

FIG. 8 illustrates an exemplary optional arrangement for granulatingpowders separately and then mixing the granules together. Theproperties, e.g. disintegration time, of the end product, e.g. tablet,may be affected by granulating components of a formulation in multiplegranulation processes vs. together in one process.

Granulation systems 801, 802 each produce granules from differentsubstances (or from the same substance but with different granulationparameters such as compaction force or size of accepted granules). Eachsystem has its own means 811, 812 of adjusting the granulationparameters. The accepted granules from each granulation system are ledthrough a conveyor 803, 804 to a granule mixing device that has means806, 807 to control the amount of each of the granules in the final mix.The mixing device may also have granule mixing means 808 to mix thegranules together before the granulate mass flows to the container offinal product 810 or directly to a tableting machine (not shown). Theconveyor 803, 804 in FIG. 8 is a tube that leads to the mixing device,but the conveyor may also lead the granules into an intermediary storagecontainer from which the mass may conveyed to the mixing device.

FIG. 9 illustrates a simple device for measuring flowability of powderor granulate mass. Devices of different sizes are used for determiningdifferent degrees of flowability. The degree of flowability may besufficient, good, very good or excellent.

The device for determining sufficient flowability has a smooth plasticsurface cone 900 with a height 901 of 45 millimeters and with cone angle902 of approximately 59 degrees and a round aperture 903 whose diameteris 12 millimeters. The length of tube 904 is 23 mm. In a flowabilitytest procedure, the cone is filled with powder or granulate mass whilethe round aperture 903 is kept closed. The aperture is opened, cone isknocked lightly to start the flow and the flow of the powder through theaperture by mere gravitation force is observed. Additional shaking orother kind of movement of the cone during the test is not allowed. Thematerial passes the flowability test if the cone substantially empties.“Substantial” here means that at least 85%, 90% or 95% of the powderleaves the cone.

The device for determining good flowability using the test procedureexplained above has a smooth glass surface cone 900 with a height 901 of50 millimeters and with cone diameter 905 of 70 mm and a round aperture903 whose diameter is 7 millimeters. The length of tube 904 is 70 mm.

The device for determining very good flowability has a smooth plasticsurface cone 900 with a height 901 of 35 millimeters and with conediameter 905 of 48 mm and a round aperture 903 whose diameter is 4millimeters. The length of tube 904 is 50 mm.

The device for determining excellent flowability has a smooth plasticsurface cone 900 with a height 901 of 40 millimeters and with conediameter 905 of 55 mm and a round aperture 903 whose diameter is 3millimeters. The length of tube 904 is 60 mm.

Using the above mentioned or other embodiments of the present invention,it is possible to produce granules that have one or multiple of somedesirable general characteristics, e.g. good flowability, goodcompressibility, good tabletability, quick disintegration time of atablet and high drug load. We have observed that those characteristicsare applicable to many APIs and excipients. Thus, some potentiallytime-consuming and expensive parts of the drug formulation designprocess of prior art may be avoided with many APIs. The embodimentsshown are also relatively cost-efficient to build and use. For example,it is possible to build an arrangement that is capable of producingseveral kilograms or tens of kilograms of granules per hour. The processis also relatively simple and easy to control in comparison to e.g. wetgranulation methods of prior art. In the shown embodiments, there arefew parameters that may need to be adjusted.

Percentage (%) values given herein are by weight unless otherwisestated.

Mean values are geometric mean values unless otherwise stated.

The examples below describe characteristics of some typical granules andtablets achievable using the embodiments of the present invention.

EXAMPLES

To observe the characteristics of the granulate mass of variousembodiments of the invention and their tabletability, a series of testshas been conducted. In all tests, method and apparatus described in thisdocument (e.g. FIG. 1 b and FIG. 4) has been used. The gas flow rate ofthe apparatus was adjusted so that the fractionating effect of the gasflow resulted in a granulate mass that had good, very good or excellentflowability. The gas flow rate in the tests was achieved operating thesuction fan (BUSCH™ Mink MM 1202 AV) of the system at a default speed ofapproximately 1860 RPM. With some materials, the speed was altered fromthe default to achieve desired quality of the granulate mass. Thecompaction force of the roller compactor was adjusted to producegranules with optimal tableting characteristics. The force used wasrecorded as kilonewtons as indicated by the roller compactor (HOSOKAWABepex Pharmapaktor L200/50P) used in the tests. The diameter of therolls of the compactor is 200 mm and the working width of the rolls is50 mm. The thickness of the ribbon produced by the compactor is about 4mm. The rotating speed of the rolls is typically between 10 and 12 RPM.The exact rotating speed is adjusted by the roller compactor to achievethe desired compaction force. The default mesh size of the flakecrushing screen is 1.00 mm. In some experiments, the mesh size of theflake crushing screen was altered from the default.

Unless specified differently, a rotating device as shown in FIG. 4operating at about 100 RPM was used as the fractionating means of theapparatus of the tests. The default size of apertures in the cylinder ofthe rotating means was 1.5 mm.

In all tableting tests, 0.25% of magnesium stearate was added to thegranulate mass prior to tableting as a lubricant.

Maize starch used in the tests was estimated to have particle sizebetween 5 and 30 micrometers.

The tensile strength of the tablets has been measured using a measuringdevice of make MECMESIN™ (Mecmesin Limited, West Sussex, UK) and modelBFG200N.

The particle size distribution of granulate mass was measured usingstack of sieves. In the measurements, the stack of four sieves wasshaken for 5 minutes using an Electromagnetic Sieve Shaker(manufacturer: C.I.S.A Cedaceria Industrial, S.L, model: RP 08) withpower setting 6. The opening sizes of the sieves used were 850 μm, 500μm, 250 μm and 106 μm.

Tableting Example 1 90% Acebutolol HCl

A powder mass of 5.0 kg having 90% of acebutolol HCl powder (meanparticle size 27 micrometers) and 10% of starch was mixed. Compactionforce of 40 kN was used to compact mass into granules having mean sizeof 877 micrometers and standard deviation of 1.421 after fractionation.The loose bulk density of the resulting mass was 0.68 g/ml and the masshad good flowability. Round tablets of 10 mm diameter and 500 mg ofweight were created using tableting force of 6-8 kN. The average tensilestrength of the tablet was 80N (N=10). Tablet disintegration time wasobserved to be about 6.5 minutes in water of approximately bodytemperature.

Tableting Example 2 20% Fluoxetine HCl

A powder mass having 20% (2.24 kg) of Fluoxetine HCl (Manufacturer:SIFAVITOR SpA, Casaletto Lodigiano. Italy. Batch no. 2700/01/06), 64%(7.168 kg) of microcrystalline cellulose (EMCOCEL CAS No. 9004-34-6,batch 5S3682) and 16% (1.792 kg) of maize starch (CERESTAR Mat. no.03401 batch 01015757) was mixed. Compaction force of 35 kN was used tocompact mass into granules having mean size of 461 micrometers andstandard deviation of 2.358 after fractionation. The mesh size of theflake crushing screen was set to 1.25 mm. The loose bulk density of theresulting mass was 0.595 g/ml and the mass had good flowability. Roundtablets of 6 mm diameter and 112 mg of average weight (N=10, standarddeviation=1.89%) were created using maximum tableting force thatproduced no capping. The average tensile strength of the tablet was 44 N(N=10, standard deviation=11.17%). Tablet disintegration time wasobserved to be about 10 seconds in water of approximately bodytemperature.

Tableting Example 3 60% Paracetamol

A powder mass of approximately 4.0 kg having 60% of paracetamol finepowder (Manufacturer: Mallinckrodt Inc.—Raleigh (USA)—Batch 78459060563,59% of particles smaller than 20 micrometers, 96% of particles smallerthan 75 micrometers), 20% of microcrystalline cellulose (EMCOCEL CAS No.9004-34-6, batch 5S3689, 50% of particles smaller than 71 micrometers)and 20% of maize starch (CERESTAR Mat. no. 03401, batch 01015757) wasmixed. Compaction force of 30 kN was used to compact the mass intogranules having mean size of 645 micrometers and standard deviation of1.464 after fractionation. The mesh size of the flake crushing screenwas set to 1.00 mm. The bulk density of the resulting mass was 0.586g/ml and the mass had good flowability. Round convex tablets of 10 mmdiameter and 454 mg of average weight (N=10, standard deviation=0.6%)were created using maximum tableting force that produced no capping.This was a very good result since hitherto it has been considereddifficult, if not impossible, to produce high load tablets ofparacetamol by compression of granulates prepared using dry granulationmethods. The average tensile strength of the tablet was 49 N (N=10,standard deviation=12.73%). Tablet disintegration time was observed tobe less than a minute in water of approximately body temperature.

Tableting Example 4 90% Sodium Valproate

A powder mass of 5.56 kg having 90% of Sodium valproate (Manufacturer:Chemische Fabrik Berg), 5% of hypromellose (PHARMACOAT 606, batch5115055) and 5% of maize starch (CERESTAR Mat. no. 03401, batch01015757) was mixed. Compaction force of 35 kN was used to compact massinto granules having mean size of 550 micrometers and standard deviationof 1.686. The mesh size of the flake crushing screen was set to 1.25 mm.The loose bulk density of the resulting mass was 0.532 g/ml and the masshad good flowability. Round convex tablets of 12 mm diameter and 560 mgof average weight (N=10, standard deviation=1.29%) were created usingmaximum tableting force that produced no capping. The average tensilestrength of the tablet was 84 N (N=10, standard deviation=11.80%).Because of the slow-release characteristics introduced by hypromelloseas excipient, tablet disintegration time was observed to be 40 minutesin water of approximately body temperature.

Tableting Example 5 50% Ketoprofen

A powder mass of approximately 8.0 kg having 50% of ketoprofen(Manufacturer: Ketoprofen S.I.M.S. Società italiana medicinaliScandicci, batch 121.087, 79% or particles smaller than 60 micrometers)and 50% of maize starch (CERESTAR Mat. no. 03401, batch SB4944) wasmixed. Compaction force of 40 kN was used to compact the mass intogranules having mean size of 900 micrometers and standard deviation of1.418. The mesh size of the flake crushing screen was set to 1.00 mm.The loose bulk density of the resulting mass was 0.625 g/ml and the masshad good flowability. Round convex tablets of 6 mm diameter and 94 mg ofaverage weight (N=10, standard deviation=1.94%) were created usingmaximum tableting force that produced no capping. The average tensilestrength of the tablet was 39 N (N=10, standard deviation=14.56%).Tablet disintegration time was observed to be about 10 seconds in waterof approximately body temperature.

Tableting Example 6 80% Metformin HCl

Approximately 4.0 kg of powder mass having 100% of metformin HCl(Supplier: SIMS trading (Firenze, Italy), batch 21.039) was compactedusing compaction force of 35 kN to produce granules having mean size of668 micrometers and standard deviation of 1.554. The mesh size of theflake crushing screen was set to 1.00 mm. The loose bulk density of theresulting mass was 0.694 g/ml and the mass had good flowability.Separately, excipient granules containing 70% of microcrystallinecellulose (EMCOCEL CAS No. 9004-34-6, batch 5S3689) and 30% of maizestarch (CERESTAR Mat. no. 03401, batch 01015757) was mixed andgranulated using the same compaction force. Then 80% of metformingranules were mixed with 20% of excipient granules and compressed intotablets. Round convex tablets of 12 mm diameter and containing 500 mg ofmetformin were created using maximum tableting force that produced nocapping. The average tensile strength of the tablet was 59 N (N=3).Tablet disintegration time was not measured.

In addition to tableting examples, compressibility and flowability ofgranulate mass of embodiments of the invention was tested by measuringthe Hausner ratio of the mass and observing the flowability of the mass.Methods usable for calculating Hausner ratio and observing flowabilityof the mass have been described earlier in this disclosure.

Flowability Example 1 100% Paracetamol

A powder mass of 4.0 kg having 100% paracetamol (Manufacturer:Mallinckrodt Inc.—Raleigh (USA)—Batch 6088906C107) was compacted usingcompaction force of 12 kN and flake crushing screen mesh size of 1.00 mminto granules having mean size of 708 micrometers and standard deviationof 1.349 after fractionation. 0.58% of the granules of the mass haddiameter of smaller than 106 micrometers. The bulk density of theresulting mass was 0.610 g/ml and tapped bulk density was 0.758 g/ml.The Hausner ratio of the mass was calculated to be 1.24. Despite therelatively high compressibility as indicated by the Hausner ratio, theflowability of the mass was observed to be excellent.

Flowability Example 2 90% Metformin HCl

A powder mass having 90% (4.0 kg) of Metformin (METFORMIN HYDROCHLORIDEUSP, BATCH N. 17003742, USV LIMITED, B.S.D. Marg. Govandi, Mumbay 400088, INDIA), 8% (356 g) of microcrystalline cellulose (EMCOCEL CAS No.9004-34-6 Batch 5S3682) and 2% (88 g) of maize starch (CERESTAR Mat. no.03401, batch 01015757) was mixed. Compaction force of 30 kN, flakecrushing screen mesh size of 1.00 mm and suction fan speed of 2100 RPMwas used to produce granules having mean size of 477 micrometers andstandard deviation of 2.030 after fractionation. 11.0% of the granulesof the mass had diameter of smaller than 106 micrometers. The loose bulkdensity of the resulting mass was 0.581 g/ml and tapped bulk density was0.714 g/ml. The Hausner ratio of the mass was measured to be 1.23.Despite the relatively high compressibility as indicated by the Hausnerratio, the flowability of the mass was observed to be excellent. Whenexperimenting with metformin, the inventors have also made a surprisingobservation that although 100% metformin fine powder exhibits heavyagglomeration (forming large, hard agglomerates) when stored in roomtemperature and ambient humidity, 100% metformin granules made of suchpowder using a method of the invention show practically no suchagglomeration during storage time.

Flowability Example 3 Excipient

A powder mass of approximately 3.0 kg containing 70% of microcrystallinecellulose (EMCOCEL CAS No. 9004-34-6 Batch 5S3689) and 30% of maizestarch (CERESTAR Mat. no. 03401, batch 01015757) was mixed. Compactionforce of 16 kN and flake crushing screen mesh size of 1.00 mm was usedto produce granules having mean size of 318 micrometers and standarddeviation of 2.159 after fractionation. 19.6% of the granules of themass had diameter of smaller than 106 micrometers. The loose bulkdensity of the resulting mass was 0.379 g/ml and tapped bulk density was0.510 g/ml. The Hausner ratio of the mass was measured to be 1.35.Despite the high compressibility of the mass as indicated by the Hausnerratio, the flowability was observed to be excellent.

Flowability Example 4 20% Ketoprofen

A powder mass of approximately 4.0 kg containing 20% of ketoprofen(S.I.M.S. Società italiana medicinali Scandicci, batch 121.087) and 80%of microcrystalline cellulose (EMCOCEL CAS No. 9004-34-6 Batch 5S3689)was mixed. Compaction force of 24 kN and flake crushing screen mesh sizeof 0.71 mm was used to produce granules. When the suction fan speed ofthe system was set at 1980 RPM, the mean size of the accepted granuleswas 304 micrometers and standard deviation was 2.275 afterfractionation. 23.0% of the mass had particle size smaller than 106micrometers. The loose bulk density of the mass was 0.510 g/ml andtapped bulk density was 0.676 g/ml. The Hausner ratio of the mass wasmeasured to be 1.325. The flowability of the mass was observed to besufficient. When the suction fan speed of the system was set at 2400RPM, the mean size of the accepted granules was 357 micrometers andstandard deviation was 2.121 after fractionation. 13.7% of the mass hadparticle size smaller than 106 micrometers. The loose bulk density ofthe mass was 0.521 g/ml and tapped bulk density was 0.714 g/ml. TheHausner ratio of the mass was measured to be 1.371. The flowability ofthe mass was observed to be excellent. This example shows that byvarying the gas flow rate of the system, granulate mass with differentflow characteristics may be obtained. This example also indicates that,contrary to what is taught in prior art, e.g. U.S. Pat. No. 6,752,939,the Hausner ratio doesn't necessarily predict the flowability of thegranulate mass. For example, the granule size distribution of thegranular mass may have greater effect on flowability than thecompressibility of the granulate mass. Good compressibility andflowability may thus co-exist in the same granulate mass.

CAPACITY EXAMPLE

The embodiments described in this disclosure are capable of producingsignificant amounts of granulate mass. In a capacity test of oneembodiment comprising the fractionating device of FIG. 4, 5.98 kg ofParacetamol (7845 Paracetamol Fine Powder—Mallinckrodt Inc.—Raleigh(USA)—Batch 7845906C563), 10.69 kg of Microcrystalline Cellulose (CASno. 9004-34-6—JRS PHARMA LP—Patterson (USA)—Batch 5S3689), 37.10 kg ofmaize starch (CERESTAR Mat. n. 03401 Batch 01015757), 12.19 kg oflactose (LACTOSE MONOHYDRATE—DMV International Pharmatose 80M DP5500Batch 10209285 906535704), 34.04 kg of cellulose (“Technocel”—CFFGmbH—Gehren Germany—Batch G13060620) were mixed and granulated usingcompaction force of ca. 40 kN and suction fan speed of 2160 RPM. Theapparatus was running for two hours and 38 minutes producing 94.66 kg ofgranules which had at least good flowability characteristics.

Fractionating Example 1

A powder mass of approximately 5.0 kg containing 50% of microcrystallinecellulose (EMCOCEL CAS No. 9004-34-6 Batch 5S3689) and 50% of maizestarch (CERESTAR Mat. no. 03401, batch 01015757) was mixed andgranulated. Reprocessing of the rejected fraction was prevented in thegranulation process. To achieve this, the mass to be processed wasmanually fed to the intermediate vessel (107 in FIG. 1 b) from where itwas conveyed to the compactor (110 in FIG. 1 b) by opening the valve(109 in FIG. 1 b) before starting the process. The process was thenstarted and the mass of 5.0 kg was granulated and fractionated. Duringthe processing, the valve (109 in FIG. 1 b) was kept shut to preventre-processing of the rejected fraction. Compaction force of 40 kN andflake crushing screen mesh size of 1.00 mm was used to produce granuleshaving mean size of 523 micrometers (standard deviation 1.70) afterfractionation. The test run produced 1630 g (32.6%) of acceptedgranules. A SEM image of the surface of an accepted granule is shown inimage 291 of FIG. 2 i. The rest of the mass was rejected by thefractionating device. 4.0% of the granules/particles of the acceptedmass had diameter of smaller than 106 micrometers. The loose bulkdensity of the resulting mass was 0.56 g/ml and tapped bulk density was0.641 g/ml. The Hausner ratio of the mass was measured to be 1.15. Theflowability of the accepted fraction was observed to be excellent. Onthe other hand, the flowability of the rejected fraction was observed tobe insufficient.

The rejected fraction contained 16.4% of granules larger than 250micrometers whereas the accepted fraction contained 92% of granuleslarger than 250 micrometers.

To observe the tabletability of the accepted fraction of the granulatemass, 0.5% of magnesium stearate was added to the mass and tablets ofaverage weight of 588 mg were produced. The average tensile strength ofthe tablet (N=6) was measured to be 23.56N and standard deviation was1,308. The disintegration time of the tablet was observed to be about 12seconds.

Fractionating Example 2

A powder mass of approximately 4.0 kg containing 50% of microcrystallinecellulose (EMCOCEL CAS No. 9004-34-6 Batch 5S3689) and 50% of maizestarch (CERESTAR Mat. no. 03401, batch 01015757) was mixed andgranulated. Unlike in the above examples, a fractionating deviceaccording to the embodiments of FIGS. 1 a and 3 of this disclosure wasused in the fractionating step of the process. Reprocessing of therejected fraction was prevented in the granulation process. To achievethis, the mass to be processed was manually fed to the intermediatevessel (107 in FIG. 1 a) from where it was conveyed to the compactor(110 in FIG. 1 a) by opening the valve (109 in FIG. 1 a) before startingthe process. The process was then started and the mass of 4 kg wasgranulated and fractionated. During the processing, the valve (109 inFIG. 1 a) was kept shut to prevent re-processing of the rejectedfraction. Compaction force of 16 kN and flake crushing screen mesh sizeof 1.00 mm was used to produce granules having mean size of 437micrometers (standard deviation 2.42) after fractionation. The test runproduced 670 g (16.75%) of accepted granules. The rest of the mass wasrejected by the fractionating device. 20.9% of the granules/particles ofthe accepted mass had diameter of smaller than 106 micrometers. Theloose bulk density of the resulting mass was 0.455 g/ml and tapped bulkdensity was 0.568 g/ml. The Hausner ratio of the mass was measured to be1.248. Despite the high compressibility of the accepted mass asindicated by the Hausner ratio, the flowability was observed to beexcellent. On the other hand, the flowability of the rejected fractionwas observed to be insufficient.

The rejected fraction contained 7.1% of granules larger than 250micrometers whereas the accepted fraction contained 68.4% of granuleslarger than 250 micrometers.

To observe the tabletability of the accepted fraction of the granulatemass, 0.5% of magnesium stearate was added to the mass and tablets ofaverage weight of 584 mg were produced. The average tensile strength ofthe tablet was measured to be 63.34N and standard deviation was 6.78(N=6). It is noteworthy that the tensile strength of the tablet issignificantly higher than in fractionating example 1. The disintegrationtime of the tablet was observed to be about 12 seconds.

To a person skilled in the art, the foregoing exemplary embodimentsillustrate the model presented in this application whereby it ispossible to design different methods, systems, granules and tablets,which in obvious ways utilize the inventive idea presented in thisapplication.

The foregoing references set forth in the specification are herebyincorporated by reference.

The invention claimed is:
 1. A fractionating device for separatingaccepted granules from a compacted mass by entraining fine particlesand/or small granules in a gas stream, the fractionating devicecomprising: a rotating device having a feed end for input of thecompacted mass, an outlet for accepted granules and apertures throughwhich fine particles and/or small granules are entrained, substantiallyalong the axis of rotation of which rotating device the compacted massflows inside the rotating device in said gas stream; wherein thedirection of the flow of the gas stream has a component which iscontrary to that of the direction of flow of the compacted mass, andwherein the axis of rotation of the rotating device is transverse to theeffect of gravity on the compacted mass or is tilted so as to provide acomponent of gravitational assistance or resistance to the flow of thecompacted mass inside the rotating device.
 2. A device according toclaim 1, wherein the direction of the flow of the gas stream issubstantially contrary to that of the direction of flow of the compactedmass.
 3. A device according to claim 1, in which movement of thecompacted mass along the axis of the rotating device is guided by meansof a spiral structure.
 4. A device according to claim 1, wherein therotating device is a cylinder.
 5. A device according to claim 1, whereinthe rotating device is a cone.
 6. A fractionating device according toclaim 1, wherein the rotating device is mounted for rotation about anaxis; and the fractionating device further includes an input for the gasstream near the outlet of the rotating device and an aperture forrejected fine particles and/or small granules.
 7. A fractionating deviceas recited in claim 6, wherein a direction of output at the aperture forthe rejected fine particles and/or small granules is substantiallytransverse to the axis of rotation of the rotating device.
 8. Afractionating device according to claim 1, wherein the rotating devicehas means for mounting the rotating device for rotation about an axis;and means for input of the gas stream to flow in a direction that issubstantially contrary to a direction of flow of the compacted mass. 9.A fractionating device according to claim 1, wherein the rotating devicecomprises at least one structure for guiding the compacted mass insidethe rotating device.
 10. A fractionating device according to claim 1,wherein the axis of rotation of the rotating device is transverse to theeffect of gravity on the compacted mass.
 11. A fractionating deviceaccording to claim 1, wherein a component of gravitational assistance orresistance may be provided by tilting the axis of rotation of therotating device.